ARTICLE IN PRESS

Respiratory Medicine (2005) 99, 152–170

Past, present and future—b2-adrenoceptor agonists in asthma management

Malcolm R. Searsa,Ã, Jan Lo¨tvallb aDepartment of Medicine, McMaster University and Firestone Institute for Respiratory Health, St Joseph’s Hospital, 50 Charlton Avenue East, Hamilton, Ont., L8N 4A6 Canada bThe Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Go¨teborg University, Sahlgrenska University Hospital, Bruna Stra˚ket 11, S-413 45 Go¨teberg, Sweden

Received 19 December 2003; accepted 5 July 2004

KEYWORDS Summary The b-adrenoceptor agonists (b-agonists) have been used to relieve Asthma; bronchoconstriction for at least 5000 years. b-agonists are based on adrenaline and b2-agonist; early forms, such as isoprenaline, lacked bronchial selectivity and had unpleasant Formoterol; side effects. Modern b-agonists are more selective for the b2-adrenoceptors (b2- Salbutamol; receptors) located in bronchial smooth muscle and have less cardiotoxicity. Salmeterol Traditional b2-adrenoceptor agonists (b2-agonists), such as salbutamol, terbutaline and fenoterol, were characterised by a rapid onset but relatively short duration of action. While valuable as reliever medication, their short duration gave inadequate night-time relief and limited protection from exercise-induced bronchoconstriction. b2-agonists with longer durations of action, formoterol and salmeterol, were subsequently discovered or developed. When combined with inhaled corticosteroids they improved lung function, and reduced symptoms and exacerbations more than an increased dose of corticosteroids. However, tolerance to the bronchprotective effects of long-acting b2-agonists and cross-tolerance to the bronchodilator effects of short-acting b2-agonists is apparent despite use of inhaled corticosteroids. The role of b2-receptor polymorphisms in the development of tolerance has yet to be fully determined. Formoterol is unique in having both a long-lasting bronchodilator effect ð412 hÞ and a fast onset of action (1–3 min from inhalation), making it effective both as maintenance and reliever medication. The recent change in classification from short- and long-acting b2-agonists to rapid-acting and/or long-acting agents reflects the ongoing evolution of b2-agonist therapy. r 2004 Elsevier Ltd. All rights reserved.

ÃCorresponding author. Tel.: +1-905-522-1155x3286; fax: +1-905-521-6132. E-mail address: [email protected] (M.R. Sears).

0954-6111/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2004.07.003 ARTICLE IN PRESS b2-agonists in asthma management 153

Introduction Development of non-selective b-agonists

Asthma is a serious public health problem, being Adrenaline one of the most common diseases in industrialised countries. There is convincing evidence that the Modern sympathomimetic drugs derive from the prevalence and morbidity of asthma are increas- discovery of a bronchodilating ‘adrenal substance’ 1,2 ing. In the USA, 14 million adults and 5.2 million by Solis-Cohen in 19009 and the joint isolation of children were affected by asthma in the mid- the active agent, adrenaline, by John Abel in 1899 1990s—an increase from the 1980 figures of 6.7 and by Jokichi Takamine in 1901. By relaxing 3 million and 4 million, respectively. Costs related to bronchial smooth muscle, in preparation for the asthma were estimated to reach $14.5 billion in the increased ventilation needed for ‘flight or fight’, 3 USA by the year 2000. 1ncreases such as these endogenous adrenaline offers a potent and fo- have led to greater awareness of the importance of cussed treatment for the breathing difficulties patient and physician education—especially re- associated with asthma. garding the risk factors for asthma and the Adrenaline (epinephrine; Fig. 1)10 was initially treatment strategies available. given parenterally, then by aerosol, and was widely Since inflammation of the airway tissues is used in the treatment of asthma for at least 35 considered to be the main mechanism in the years following its discovery. However, although development and maintenance of asthma, limiting inhaled adrenaline gave patients rapid relief of exposure to inflammatory triggers and reducing the asthma symptoms, concerns arose about possible inflammatory process using anti-inflammatory cardiotoxicity and the development of tolerance.11 drugs are the main thrusts of the modern manage- The overuse of nebulised adrenaline spray that 4,5 ment of asthma. The first-line anti-inflammatory resulted from tolerance was linked with a fivefold drugs, inhaled corticosteroids (ICS), may be ade- increase in mortality in patients with asthma who quate to fully control symptoms in mild cases. used the spray compared with non-users.11 Thus, However, for many patients, additional drug ther- there was a need for drugs with the bronchodilating apy, typically bronchodilators that relax airway effect of adrenaline but which had greater selec- smooth muscle, is needed for the relief of acute tivity for airway smooth muscle and correspond- 6 symptoms. b2-adrenoceptor agonist bronchodila- ingly fewer side effects. tors ðb2-agonists) are the most effective and widely used drugs to produce rapid reversal of broncho- constriction. Although traditionally classified by Isoprenaline their duration of action, as short-acting and long- acting b2-agonists, such classifications may not now The first pure b-agonist to be synthesised was reflect the full therapeutic relevance of these isoprenaline (isoproterenol; Fig. 1), developed in agents. the 1940s. Although an effective bronchodilator b-adrenoceptor agonists (b-agonists), one of and more selective than adrenaline,12 isoprenaline the oldest classes of drugs used in medicine, was still associated with substantial extra-pulmon- act by mimicking the effects of adrenaline. ary side effects, such as palpitations, tachycardia Sympathomimetic agents were used in Chinese and headache. Isoprenaline, like adrenaline, is a herbal medicines to relieve breathing difficulties catecholamine, a class of drugs characterised by as early as 3000 BC. The active material, an chemical and metabolic instability resulting in a alkaloid now identified as ephedrine, was originally short duration of action.13 extracted from the plant Ephedra equisetina and The discovery that adrenaline and isoprenaline known as Ma Huang.7 However, ephedrine was only had different physiological properties led to a introduced into western medicine as recently as greater understanding of the nature of their 8 1924. The b2-agonists have become standard specificity and allowed more selective drugs to be bronchodilators for emergency room treatment of developed. Ahlquist14 noted that adrenaline was asthma, and as day-to-day reliever medication. more potent than isoprenaline in smooth muscle Their role in maintenance treatment to control that responded by contraction, but the opposite asthma in conjunction with other medications, was true in smooth muscle that responded by particularly ICS, has been re-evaluated over the relaxation. He suggested that tissues contained past decade. This paper is a non-systematic review different types of adrenergic receptors and that of the evolution of b-agonists and provides a the two drugs demonstrated different properties by perspective on their current role in the manage- acting as agonists at these different receptors. This ment of asthma. initial classification introduced the concept of ARTICLE IN PRESS

154 M.R. Sears, J. Lo¨tvall

Figure 1 Chemical structure of selected b-agonists.10 Reproduced with kind permission from the Australian Medical Association. alpha-(a) and beta-(b) adrenoceptors, with a- identified in the heart and intestinal smooth receptors associated with vasoconstriction, stimu- muscle, while the b2-receptor was identified lation of the uterus and intestinal relaxation, and primarily in bronchial, vascular and uterine smooth b-receptors with vasodilation, bronchodilation and muscle. Isoprenaline was a non-selective b-agonist myocardial stimulation. (no a-receptor activity but activity at both b1- and Although adrenaline had both a- and b-receptor b2-receptors), which explained its side-effect agonist activity, isoprenaline had only b-receptor profile. Isoetharine improved the benefit-to-risk agonist properties. However, although this ac- ratio as a result of low a-receptor activity and counted for the different side-effect profiles of enhanced b2-receptor activity, as did the more the two drugs, explaining why some of the side potent and longer-acting resorcinol analogue orci- effects (such as urinary retention and hyperten- prenaline (metaproterenol) introduced in the early sion) were associated only with adrenaline, it did 1970s. However, both isoetharine and metaproter- not explain the undesirable side effects of iso- enol had undesirable cardiac side effects due to prenaline. action on b1-receptors. Furthermore, the presence An analogue of isoprenaline, isoetharine (1951), of a significant population of b2-receptors in showed increased bronchodilator selectivity and cardiac muscle meant that some cardiac stimula- duration of effect, but still had undesirable cardiac tion was inevitable even with a totally selective b2- side effects. Only with the discovery that there was agonist.16 Use of small, inhaled doses of highly 15 more than one type of b-receptor did greater selective b2-agonists was expected to result in selectivity become possible. The b1-receptor was preferential activation of pulmonary b2-receptors, ARTICLE IN PRESS b2-agonists in asthma management 155 with minimal side effects from the drug reaching with the action of other ligands,30 possibly due to the systemic circulation and peripheral tissues.17 continued receptor occupation. However, to target drugs more effectively, more Ligands bind within the hydrophobic core of the needed to be known about the b2-receptor and its receptor, with critical interactions taking place mechanism of activation. between chemical groups of the agonist and certain key residues.24 The three-dimensional arrangement of these interacting chemical groups has implica- The b2-receptor tions for structural changes resulting from poly- morphisms in the receptor, and may also influence The b-receptor is a glycoprotein embedded in the the development of tachyphylaxis. plasma membranes of a number of cell types. Three distinct subtypes of b-receptors are now known, b1; b2; b3; found predominately in cardiac muscle, b-receptor polymorphisms airway smooth muscle and adipose tissue, respec- 18 tively. The b2-receptor is composed of 413 amino The gene encoding the human b2-receptor is a gene acid residues arranged in seven membrane-span- without introns, located on the long arm of ning alpha-helices.19 These helices form a three- chromosome 5, and has a coding block of 1239 dimensional binding site accessible via the extra- nucleotides.31–33 Nine variations occur in the cellular aqueous biophase.20 Approximately 80% of normal population.31,32,34 These polymorphisms the b-receptors in the lungs are of the b2- are point mutations distributed throughout the subtype.21 However, there is a homology of 54% coding block and are found at nucleotide positions 22 34 between the human b1- and b2-subtypes, which 46, 79, 100, 252, 491, 523, 1053, 1098 and 1239. may result in any highly selective b2-agonist having Five are degenerate and the remaining four, at an effect on b1-receptors. nucleotides 46, 79, 100 and 491, result in single Ninety percent of the b2-receptors in the lungs amino acid substitutions at positions 16 (arginine to are thought to be located in the alveolar wall,23 glycine), 27 (glutamine to glutamate), 34 (valine to with the remainder found on smooth muscle cells methionine) and 164 (threonine to isoleucine)33,34 and in the membranes of epithelial, endothelial (Fig. 2). Amino acids 16 and 27 lie in the and mast cells.24 Smooth muscle cells may each extracellular N-terminal domain while 34 and 164 25 33 contain 30 000–40 000 b2-receptors. No difference are in the transmembrane spanning regions. has been reported in the number of receptors found The most common polymorphisms are at amino in healthy subjects and those with asthma, acid positions 16 and 27 whereas that at 34 is rare, although an inverse relationship has been reported with an allele frequency of o1%:32,35 The poly- between lung b2-receptor density and forced morphism at 164 is uncommon, the heterozygous 25 expiratory volume in 1 s (FEV1) (% predicted). Of state having been found in only 3–5% of the relevance to the occurrence of cardiac side effects, population.32,35 The frequency of the position 16 however, is that up to 40% of b-receptors in the and 27 variants differs among white, black and ventricles and up to 55% in the atria are also of the Asian populations.32,36 AII these polymorphisms 26 b2-subtype. have been found with equal frequency in both healthy individuals and patients with asthma and are thus unlikely to be the cause of asthma per se. b-receptor activation However, they may influence the phenotype of the illness once it is expressed,33 by acting as disease b-receptor activation increases levels of intracel- modifiers, altering baseline airway function or the 35 lular cyclic adenosine monophosphate (cAMP) via response to b2-agonists. G-protein activation of adenyl cyclase.27 The cAMP The cellular phenotypes of these polymorphisms is then thought to influence key regulatory proteins are shown in Table 1. The Ile164 variant shows (cAMP-dependent protein kinases) involved in the altered agonist binding and altered receptor down- control of muscle tone, inhibit calcium ion release regulation following agonist simulation.37 Gly16 from intracellular stores, reduce calcium ion entry and Gln27 are associated with increased down- into the cells, and sequester intracellular calcium regulation following agonist exposure, while Glu27 ions.17 The result is to bring about relaxation of the appears to be protective against downregulation. central and peripheral airway smooth muscle and Several studies have shown an association between hence bronchodilation. Prolonged receptor binding polymorphisms 16 and 27 and airway responsive- may however lead to desensitisation through ness. Hall et al.38 showed that patients with asthma uncoupling or sequestration28,29 and may interfere who were homozygous for Glu27 had less reactive ARTICLE IN PRESS

156 M.R. Sears, J. Lo¨tvall

Figure 2 Primary amino acid sequence and proposed membrane topography of the human b2-receptor. Reprinted with permission from Blackwell Publishing.34

Table 1 Cellular phenotypes of b2-adrenoceptor polymorphisms as determined in cell and transgenic systems. Reprinted with permission from the American Academy of Allergy Asthma and Immunology.35

Nucleic acid no. Amino acid no. Designation Phenotype

46 16 Arg16 Wild type 46 16 Gly16 Enhanced downregulation 79 27 Gln27 Wild type 79 27 Glu27 Absent downregulation 100 34 Val34 Wild type 100 34 Met34 Normal 491 164 Thr164 Wild type 491 164 Ile164 Decreased coupling, binding and sequestration airways than those who were homozygous for Kotani et al. showed that patients with asthma Gln27, showing a fourfold higher geometric mean homozygous for Gly16 had significantly ðPo0:05Þ methacholine PD20 (provocative dose causing a 20% lower airway responsiveness to inhaled salbutamol 39 fall in FEV1). Ramsay et al. also found an than those heterozygous for Arg/Gly16 or homo- association between Glu27 and decreased airway zygous for Arg16, and that those heterozygous responsiveness to histamine. ln addition, Arg16 was for Gln/Glu27 had a significantly ðPo0:05Þ later associated with increased wheeze during respira- onset of asthma than those with the wild-type tory infection.39 genes.40 Similarly, Lima et al.41 showed that Arg16 ARTICLE IN PRESS b2-agonists in asthma management 157 polymorphism is a major determinant of bronchodi- the glycine b2-receptor form being more susceptible lator response to salbutamol: patients homozygous to downregulation and the arginine form less for Arg16 had a more rapid increase in FEV1 and a susceptible when exposed to exogenous b2-agonists. higher bronchodilator response 1 h after salbutamol Jackson and Lipworth51 performed a retrospective administration than patients with the Gly16 allele. analysis of data from six placebo-controlled, rando- In a study of 23 patients with nocturnal asthma and mised, cross-over studies in an attempt to resolve 22 patients with non-nocturnal asthma, the fre- which model is applicable in patients. Their results quency of the Gly16 allele was 80% in the noctural support the dynamic model, since Arg16 polymorph- group and 52% in the non-nocturnal group ðP ¼ isms were associated with a subsensitivity of 0:007Þ with an odds ratio of 3.8 for having nocturnal response to long-acting b2-agonists. asthma and the Gly16 allele.42 Although point mutations clearly influence re- 43 Hancox et al. found no association between b2- sponse to b2-agonists, the effects of combinations receptor polymorphism and the deleterious re- of mutations into complex haplotypes must also be sponse to long-term, regular fenoterol treatment. considered. Drysdale et al.52 investigated response In addition, Lipworth et al.44–46 showed in a number to salbutamol in 121 patients with asthma. Twelve of studies that polymorphism at codon 16 or 27 did different haplotypes were expressed within the not influence the degree of functional antagonism group. For the five most common in vivo, b2-agonist exhibited by formoterol, salmeterol or terbutaline. response was significantly related to the patients’ In contrast, Taylor et al.47 found that among genotype ðP ¼ 0:007Þ: Haplotype pair 4/6 showed patients homozygous for Arg16, the frequency of the greatest increase in FEV1 while 4/4 showed the major exacerbations more than doubled during smallest response. A similar study, however, treatment with salbutamol compared with placebo showed no significant effect of haplotype on the and that the rate of exacerbations during salbuta- in vivo response to isoprenaline.53 mol treatment was five times greater than among The exact clinical implication of different poly- 48 homozygous Gly16 patients. Israel et al. also morphisms of the b2-receptor, and their impact on showed that polymorphism at codon 16 had an acute or regular treatment with b2-agonists, is not effect on the response to the regular use of yet fully elucidated. Further prospective and salbutamol: patients homozygous for Arg16 showed detailed studies of short- and long-acting b2- a decline in morning peak expiratory flow (PEF) agonists in large patient groups with different while those homozygous for Gly16 did not. receptor genotypes are needed. The Gly16 polymorphism may also determine patient susceptibility to bronchodilator desensiti- Development of more selective b -agonists sation. Tan et al.49 demonstrated a significantly 2 ðP 0:05Þ greater degree of bronchodilator desen- o The total effect of any b -agonist involved in sitisation following treatment with formoterol in 2 bronchodilation is a property of its b -receptor patients homozygous for Gly16 than in patients 2 binding affinity and its ability to induce an homozygous for Arg16. Conversely, Lee et al.50 intracellular response. The latter is due to a indicated that the Arg16 polymorphism was asso- conformational change in the receptor leading, in ciated with subsensitivity of response for bronch- turn, to one or more intracellular events. The oprotection in patients taking regular ICS. This potency of a drug is related to the amount required subsensitivity was greater for formoterol than for for a physiological response, whereas efficacy is a salmeterol.50 The different responses to formoterol term related to the drug’s ability to induce and salmeterol may reflect differences in intrinsic maximum physiological effects. Although isoprena- receptor efficacy with regard to prolonged receptor line had a high potency and high pharmacological occupancy. efficacy (Table 2), extensive interactions with b - Subsensitivity may also be influenced by endogen- 1 receptors limited its usefulness because of its ous catecholamines and their effect on basal b - 2 potential to cause cardiovascular side effects. receptor regulation. Liggett35 suggested two possi- Hence, in the 1960s more selective b -agonists, ble models of receptor kinetics. The dynamic model 2 such as fenoterol, salbutamol and terbutaline, indicated that the glycine form of b -receptor would 2 were developed. be more susceptible to downregulation by endogen- ous catecholamines, whereas the arginine form would show basal upregulation, resulting in toler- Fenoterol ance and subsensitivity upon b2-agonist exposure. The alternate, static model suggests little or no Fenoterol (Fig. 1) is a resorcinol derivative of effect of endogenous catecholamines, resulting in orciprenaline, with negligible a-receptor-stimulating ARTICLE IN PRESS

158 M.R. Sears, J. Lo¨tvall

activity. It is relatively selective for b2-receptors, Levalbuterol (R-albuterol), a single isomer of although less so than salbutamol and, possibly, salbutamol, is currently available as a nebulised terbutaline.54 Inhaled fenoterol produces superior solution in the USA. Several studies have compared bronchoprotection compared with isoprenaline.54 levalbuterol with salbutamol (racemic albuterol) Although the time to maximum effect is longer with and suggest that use of the single isomer may fenoterol, its duration of action (4–6h)isalsolonger reduce hospitalisations,59 have fewer adverse compared with isoprenaline (Table 2) and it has less effects60 and provide similar bronchodilator effects effect on heart rate.54 ln one early study, 20 of 22 at a reduced dose.61 However, other studies have patients with asthma receiving both fenoterol and indicated similar efficacy of the isomer and the isoprenaline aerosol inhalers expressed a preference racemic form,62,63 echoed by the current interna- for fenoterol.55 tional guidelines on the management of asthma.64 Further development and evaluation of enantio- mers may clarify whether there are significant Salbutamol benefits to be obtained from single isomer forms of b -agonists. Salbutamol (albuterol), developed by modifying the 2 basic catechol nucleus common to the naturally occurring adrenergic neurotransmitters adrenaline Terbutaline and noradrenaline, was introduced in 1969. Salbu- tamol is longer lasting than isoprenaline and Terbutaline (Fig. 1) is a non-catecholamine b2- isoetharine because it is not broken down by agonist related to orciprenaline. It is also resistant catechol O-methyltransferase.56 The salbutamol to degradation by catechol O-methyltransferase 65 molecule (Fig. 1) is hydrophilic and accesses the because it contains a resorcinol group. lt was specifically developed to relax the trachea without b2-receptor directly from the aqueous extracellular compartment. This results in a fast onset of action, affecting the cardiac muscle, and was first intro- 66 with effective bronchodilation occurring within duced in 1970. Bronchodilation occurs rapidly 2–3 min and peak bronchodilation within 15 min of after inhalation and effects may persist for 4–6h inhalation.57 However, the molecule binds only (Table 2). Terbutaline is useful for as-needed weakly to the receptor and quickly diffuses back medication. A prodrug of terbutaline, oral bambu- into the microcirculation. This accounts for its terol, is also an effective bronchodilator when short duration of action (4–6 h), similar to that of given orally, and has a longer duration of action 67 fenoterol (Table 2). similar to that of salmeterol. Salbutamol has negligible a-receptor activity and demonstrated a 4500-fold greater selectivity Limitations of short-acting b2-agonists between b2- and b1-receptors than any other product previously available.58 Salbutamol thus Although terbutaline and salbutamol are very overcame many of the limitations of its predeces- widely used, they have a relatively short duration sors and quickly became the most widely used and of action. Whether taken by inhalation or by popular b2-agonist. mouth, the duration of bronchodilation achieved

Table 2 Summary of some pharmacological properties of selected b2-agonists. Affinity for Efficacy at Potency at Selectivity ratio Approximate Approximate b2-receptor b2-adrenoceptors b2-adrenoceptors (b2 : b1 receptors) onset of duration of ðKiÞ (nM) (relative to (relative to action (min) action isoprenaline isoprenaline) as 100%)

Isoprenaline 200 (100) (1.0) 1:1 2–5 o20 min Salbutamol 2500 86 0.55 1:1375 2–34–6h Fenoterol — 100 — 1:120 2–44–6h Terbutaline — 65–85 —— 2–44–6h Salmeterol 53 63 8.5 1:85 000 30 412 h Formoterol 76 100 20.0 1:120 2–3 412 h

Data derived from Refs.25,58,78,141 (—denotes data not available). ARTICLE IN PRESS b2-agonists in asthma management 159 with a single dose of either drug does not exceed and salmeterol of 1 mmol=lhavebeenestimatedin 4–6 h. Although this does not affect their usefulness the periciliary fluid of the bronchi after a single for as-needed medication, it does impose limita- inhalation.20 The molecules then diffuse across the tions for patients who require continuing broncho- epithelium towards the airway smooth muscle. 70 dilator therapy to reverse airway narrowing and Formoterol is moderately lipophilic (Kr½mem 500 : 1) long-term protection from bronchospasm, e.g. and most of the inhaled dose that reaches the patients with nocturnal asthma. The need for b2- smooth muscle layer is taken up into the cell agonists with a longer duration of action was the membranes. This forms a depot from which for- impetus for the development of formoterol and moterol is thought to progressively leach out to salmeterol. interact with the b2-receptors (Fig. 3). Formoterol thus has a prolonged effect, causing bronchodilation that lasts for more than 12 h72,73 (Table 2). However, b2-agonists with long-acting properties sufficient numbers of molecules remain in the aqueous phase outside the cells to allow immediate There are currently two inhaled b2-agonists with durations of action in excess of 12 h, formoterol interaction with b2-receptors and, therefore, a fast 74 and salmeterol. Each molecule was developed to onset of bronchodilation (within 1–3min). Hence, formoterol acts as rapidly as salbutamol.75 interact specifically with the b2-receptor. Their profiles are best understood by considering their Compared with salmeterol and salbutamol, for- different physicochemical properties in the micro- moterol is a full agonist at the b2-receptor and environment of the b -receptor, including the cell results in more than 80% of maximal b2-receptor 2 71 membrane. activation. In terms of relaxing isolated human bronchi, formoterol has been found to be 4100 times more potent than salmeterol and 4300 times Formoterol more potent than salbutamol.76 Formoterol (eformoterol in the UK) is a formani- lide-substituted phenoethanolamine (Fig. 1) and Salmeterol was synthesised as part of a series of molecules systematically developed for increasing b2-recep- Salmeterol is a saligen derivative of phenylethano- tor selectivity and bronchodilator potency.68 lamine (Fig. 1) developed in the early 1980s and has Although originally developed for oral use, formo- been available clinically since 1990. When the terol was subsequently found to have an extended molecule was designed, the head group of salbuta- duration of action when taken by inhalation.69 mol was used, taking advantage of this molecule’s When b2-agonists are inhaled, high topical b2-agonist properties and minimal side-effect pro- concentrations are instantly deposited on the file on other adrenoceptors. The aliphatic side airway epithelia: concentrations of formoterol chain was extended to interact with a theoretical

Figure 3 Diagrammatic representation of the diffusion microkinetic hypothesis. Reprinted with permission from Elsevier.71 ARTICLE IN PRESS

160 M.R. Sears, J. Lo¨tvall

exosite inside or outside of the b2-receptor, to Compared with formoterol, salmeterol is a prolong the action of the salmeterol molecule.68 partial agonist at the b -receptor and therefore ( 2 The salmeterol side chain has a length of 17 A; does not result in maximal bronchodilation.70,81,82 which makes the molecule 410 000 times more Salmeterol is appropriate for use as a regular long- 58 lipophilic than salbutamol. Salmeterol therefore acting b2-agonist, but not for rapid reversion of partitions rapidly (within 1 min) into the outer airflow obstruction or for treatment of acute phospholipid monolayer of any cell membrane in its symptoms of asthma. vicinity (Kr½mem 22,500: 1), and appears to diffuse laterally along the cell membranes, at approxi- mately 2 mm=s.77 However, to diffuse through the tissue, from epithelium through the submucosa to Current use of b2-agonists the bronchial smooth muscle, salmeterol has to diffuse out of one cell membrane, to enter the Regular use and as-needed use next, to continue its diffusion. Since most salme- terol molecules are present in cell membranes, this Since the importance of inflammation in causing is a relatively slower process than that observed the symptoms of asthma was recognised, anti- with formoterol, thus explaining the slower onset inflammatory drugs, particularly ICS, have been of action of salmeterol. Furthermore, little inter- recommended for first-line maintenance treat- 83 action with b2-receptors on the interstitium may ment. Bronchodilators, such as the inhaled also contribute to the relatively slower onset of short-acting b2-agonists salbutamol (200 or 400 mg) action of salmeterol. Clinically, salmeterol does not and terbutaline (0.5 mg), are now regarded as achieve its maximum effect until approximately symptom-relieving drugs to be given on an ‘as- 30 min after inhalation, whereas formoterol, sal- needed’ basis.84 This change in usage, from a butamol and terbutaline reach clinically important regular four-times daily regimen (which, it was effects within 3 min, and close to maximum effects thought, would ‘keep the airways open’) to use within 10–15 min.57,73,75 only as needed, was catalysed by a study showing The extended duration of action of salmeterol that the regular use of the potent short-acting b2- has been explained by its long aliphatic side chain agonist fenoterol resulted in a significant deteriora- 85 acting via an exosite within the b2-recep- tion of asthma control. This deterioration was tor.24,58,78,79 Although this could explain its accompanied by a decline in lung function and extended duration of action and the molecule’s increased airway responsiveness,86 as well as more ability to ‘reassert’ its effect after multiple exacerbations,85–87 despite concurrent use of ICS. wash-out cycles, other molecules (including The regular use of salbutamol had become formoterol) also have this property of reassertion widespread as standard practice, based in large without having long side chains. Consequently, part on one very short study.88 ln this crossover the exosite hypothesis is not universally ac- study with 1 week of treatment in each arm, cepted.20 Pre-treatment of airway smooth muscle slightly higher evening PEF (measured after bronch- tissue with the pure aliphatic side chain of odilator use) and less need for reliever salbutamol salmeterol failed to block the long duration of (but overshadowed by eight puffs of regular salmeterol, which should have occurred if the treatment each day) were regarded as benefits of anchored binding was the only mechanism for its regular treatment. Extrapolation of regular use of long duration of action.80 salbutamol to the more potent agent fenoterol The plasmalemma diffusion microkinetic model, seems to have been a major reason for the outlined above for formoterol,21 also explains the epidemic of asthma mortality experienced in New activity of salmeterol by its partitioning behaviour Zealand from 1976 onwards. Subsequent work has into the plasmalemma lipid bilayer (Fig. 3). shown no advantage in patients taking salbutamol Salmeterol does not appear to cross the membrane on a regular basis over and above its use as to enter the cytoplasm, but rather remains in the needed.89 outermost monolayer, and slowly diffuses from the On the other hand, studies with the longer-acting 77 membrane (t1=2 approx 25 min at 25 1C). This b2-agonists formoterol ð12 mg delivered dose twice mechanism alone, or together with the ‘anchored daily) and salmeterol ð50 mg twice daily) have binding theory’, explains the long duration of shown that both improve lung function and increase action of salmeterol. This differs from formoterol, overall asthma control when used regularly in for which long duration of effect is explained by a combination with ICS.84 ln particular, regular use depot of formoterol molecules in cell membranes in of these agents has been shown to reduce the ICS the smooth muscle or in the tissue72,73 (Fig. 3). dose requirement and hence the potential for easy ARTICLE IN PRESS b2-agonists in asthma management 161 bruising, skin thinning, cataracts, weight gain and The choice of fluticasone dose in such studies is increased incidence of oropharyngeal side effects clearly important as a substantial proportion of the associated with prolonged high-dose ICS therapy.90 therapeutic benefit can be achieved with a total This is supported in part by a study in which 50% daily dose of 200 mg=day:97 Although it is reasonable reduction in ICS dose with concomitant salmeterol to choose an optimal ICS dose, thus avoiding under therapy was well tolerated with no significant loss treatment, little additional benefit from higher of asthma control.91 However, that study also doses would be expected as such doses would be on showed that stopping ICS treatment altogether, the plateau of the dose–response curve. while continuing salmeterol therapy, resulted in a significant ðPo0:001Þ increase in the number of asthma exacerbations. This reinforces the view Combination therapy with formoterol that although long-acting b2-agonists have a ster- oid-sparing effect when used in combination with The 12-month FACET (Formoterol And Corticoster- ICS, they do not show anti-inflammatory activity oids Establishing Therapy) study was the first and when used independently do not maintain as investigation into asthma therapy that used reduc- good asthma control. tion in the rates of severe and mild exacerbations as the primary efficacy parameters.98 The study demonstrated that adding formoterol to two Combination therapy with salmeterol different doses of budesonide reduced rates of severe and mild exacerbations per patient and Addition of a long-acting b2-agonist to ICS (combi- significantly ðPo0:05Þ improved symptom scores, nation therapy) has been demonstrated in many lung function and the need for short-acting b2- studies to be more effective in reducing asthma agonists for relief medication compared with symptoms and increasing lung function than in- increasing the dose of budesonide alone.98 When creasing the ICS dose alone. Studies in patients with formoterol was added to the lower dose of asthma who were symptomatic despite mainte- budesonide ð100 mg metered dose, twice daily), nance treatment with beclomethasone and who severe and mild exacerbations were reduced by showed bronchodilator responsiveness, have de- 26% and 40%, respectively; when the same dose of monstrated that, compared with an increased dose, formoterol was added to the higher dose of adding salmeterol to the existing dose of beclo- budesonide ð400 mg metered dose, twice daily), methasone was preferable to increasing the dose of severe and mild exacerbations were reduced by steroid alone. With combination therapy, daytime 63% and 62%, respectively. Severe and mild and night-time symptoms were better controlled, exacerbations were reduced by 49% and 37%, morning and evening PEF rates were improved, and respectively, comparing budesonide 400 mg with diurnal variation and use of relief bronchodilator 100 mg twice daily without the addition of formo- medication were reduced.92,93 terol. Hence, the FACET study demonstrated re- Patients initiated into maintenance treatment duced exacerbations with a higher dose of ICS, with a combination of salmeterol and fluticasone greater than with the addition of a long-acting b2- propionate were found to have greater improve- agonist, but the greatest benefits were seen when ments in pulmonary function and symptom control the two were combined.98 than those initiated on treatment with either Adding formoterol to ICS also appears to be at therapy alone.94 Equally, patients symptomatic least as effective in improving lung function and while receiving low-dose fluticasone propionate controlling asthma symptoms as doubling the dose ð100 mgÞ achieved significantly greater improve- of ICS. For example, when formoterol twice daily ments in lung function and symptom control and was added to beclomethasone 500 mg daily, the fewer exacerbations, when salmeterol was added increase in mean morning PEF and decreased use of to their existing dose of steroid, compared with reliever medication was significantly ðPo0:01Þ patients whose dose of fluticasone propionate was greater than for patients not taking formoterol more than doubled without the addition of salme- whose ICS dose was doubled.99 terol.95 However, a study by D’Urzo and collea- The 12-month OPTIMA (Oxis [formoterol] and gues96 demonstrated no additional benefit of Pulmicort [budesonide] Turbuhalers In the Man- salmeterol on the number of severe exacerbations agement of Asthma) study in patients with mild-to- in patients concomitantly taking optimal anti- moderate asthma also demonstrated that adding inflammatory treatments, although significant im- formoterol to maintenance treatment in patients provements in PEF, night-time awakenings and who remained symptomatic despite receiving a low reliever medication use were observed. dose of ICS, reduced exacerbations and improved ARTICLE IN PRESS

162 M.R. Sears, J. Lo¨tvall

asthma control more effectively than doubling the arisen over tolerance to regular long-acting b2- ICS dose.100 However, in steroid-naı¨ve patients, agonist therapy and whether this reduces the adding formoterol to ICS was no more effective at efficacy of rescue b2-agonists when used for rapid reducing exacerbations than ICS alone. The slight relief of symptoms. While carefully designed increase in lung function seen with formoterol studies show reduced effectiveness of short-acting represents the bronchodilator response of normal b2-agonists in increasing lung function or in rever- airways and is not of clinical significance. sing methacholine-induced bronchoconstriction, studies in the emergency room have failed to show Current treatment guidelines any significant differences in response rates to high-dose short-acting b-agonists as needed for the treatment of acute asthma in patients receiving The use of combination therapy is now reflected in 106 treatment guidelines. For adults and children over long-acting b-agonist. 5 years old with moderate and severe persistent asthma symptoms in whom control is not achieved Increased mortality associated with b- by low to moderate doses of ICS alone, addition of agonists b2-agonists with long-acting properties, such as salmeterol or formoterol, to ICS is recommended as Between 1959 and 1966, the death rate in the UK preferable to increasing the dose of ICS 4,5,64,82,83 among patients aged 5 34 years with asthma alone. – increased threefold, with similar patterns reported elsewhere.107 Since asthma had rarely been fatal before and no new environmental factors appeared Safety of b2-agonists to be involved, concerns were raised about the use of new medications, in particular pressurised Side effects of b2-agonists isoprenaline aerosols. These deaths were even- tually linked to the use of a particularly strong Side effects of b2-agonists are greatest when the formulation of isoprenaline (isoprenaline forte: five drugs are administered orally or parenterally.84 times stronger than the dose of isoprenaline Unwanted effects include muscle tremor, increases metered dose inhaler [MDI] used in other coun- in blood glucose and lactate, and decreases in tries).107 The death rate decreased following wide- 26 serum potassium and serum calcium. b2-agonists spread publicity about possible overuse of this drug can impact cardiac function (producing, for exam- and the importance of medical supervision. Iso- ple, palpitations, tachycardia and arrhythmias in prenaline was later superseded by more selective rare cases), which must be monitored. Some of b2-agonists, such as fenoterol and salbutamol. these side effects can be considered inevitable However, fenoterol subsequently became linked considering the pharmacological actions of the to a second epidemic of asthma mortality in New drugs and the widespread distribution of b2- Zealand in the late 1970s. receptors. For example, tremor results from Fenoterol MDI was introduced into New Zealand stimulation of the b2-receptors in skeletal muscle, in April 1976—the same year that the second while even the most selective drugs will have some epidemic began. Although making up less than 5% 56 effect on b2-receptors in the heart. However, of the MDI b2-agonist market in most countries, most pharmacologically predictable events appear fenoterol soon accounted for almost 30% of the 108 to be of little clinical significance in patients total MDI b2-agonist sales in New Zealand. receiving recommended doses. If the drug is given Fenoterol MDI was dispensed at 200 mg/inhalation by inhalation, many side effects are avoided as the (compared with salbutamol at 100 mg/inhalation) systemic load and thus the plasma concentration of and shows similar b2-receptor selectivity to salbu- the drug is reduced.56 Patients with more severe tamol. The somewhat greater magnitude and airway obstruction may be relatively protected duration of bronchodilation with fenoterol com- from unwanted side effects due to reduced lung pared with salbutamol may have led to a delay in absorption.101 patients recognising the severity of an attack and Tachyphylaxis to both the bronchoprotective seeking medical help.109,110 Alternatively, it was effect, and, to a lesser extent, the bronchodilator suggested that fenoterol was associated with 102,103 activity, occurs with all b2-agonists although increased mortality by increasing cardiac adverse this can be attenuated with corticosteroid ther- events.108 Findings from case–control studies of apy.104,105 The significance of such tachyphylaxis patients who died from asthma during the late has been much debated. Recent concerns have 1970s and 1980s in New Zealand were consistent ARTICLE IN PRESS b2-agonists in asthma management 163 with the hypothesis that the use of fenoterol by MDI relationship with use of asthma drugs, found an increased the risk of death in severe asth- odds ratio for death of 5.4/canister/month with ma.108,111,112 A clinical study of regular b-agonist inhaled fenoterol and 2.4/canister/month with therapy with two doses of fenoterol 0.2 mg four salbutamol compared with the reference group of times daily, demonstrated a deleterious effect on patients with asthma who did not receive any b2- airway responsiveness, lung function, and clinical agonist.117 Further analysis of this study revealed control of asthma compared with as-needed that the risk of asthma death began to escalate 85 b2-agonist treatment. This supports the hypoth- markedly at about 1.4 canisters/month of inhaled 118 84 esis that fenoterol may have increased asthma b2-agonist. Svedmyr and Lo¨fdahl argued that, severity and fuelled the epidemic of mortality.113 with the exception of nebulised and high-dose Time-trend data further supported this hypoth- fenoterol, no study has convincingly demonstrated 114 esis. Not only did the increased death rate from a connection between the use of inhaled b2- asthma in New Zealand closely follow the introduc- agonists at recommended doses and an increase in tion and use of fenoterol and decline after asthma deaths. A review of the literature on the restrictions on fenoterol, but hospital admissions clinical experience with inhaled b2-agonists con- also declined abruptly. This strongly suggests that cluded that these agents remain appropriate and the adverse effect of fenoterol was on asthma reliable treatments for patients with asthma.119 severity and not cardiac toxicity. There was no Nevertheless, the two mortality epidemics linked suggestion of a class effect of inhaled b2-agonists in with high-strength isoprenaline in the 1960s and the epidemic and no evidence that the increased with fenoterol in the late 1970s, have made most death rate may have occurred because of under- clinicians cautious in prescribing potent short- prescribing of ICS, or the influence of social factors, acting b2-agonists regularly or frequently as relie- such as unemployment.115 ver therapy. Increased mortality has also been associated with long-acting b2-agonist therapy. In a recent study of salmeterol in patients with asthma, a post-market- Tolerance to b2-agonists ing clinical trial was halted early following the discovery of a non-significant trend towards more The development of tolerance to their bronchodi- asthma-related deaths in patients taking salmeter- lator activity may be a concern with the prolonged 116 ol. African-American patients (17% of study use of b2-agonists due to receptor downregulation population), especially those not maintained on and desensitisation. Because of their longer dura- ICS, had a significantly higher risk of death. These tion of b2-receptor occupancy, formoterol and deaths led to a labelling change indicating caution salmeterol might be expected to induce even in the use of salmeterol in African American greater tolerance than the short-acting b2-ago- patients. nists. However, while a decrease in morning lung The interpretation of studies relating to asthma function (PEF) has been shown following regular morbidity and mortality, and the associations with treatment with salbutamol, no tendency to develop 120,121 potent or frequent use of inhaled short-acting b2- tolerance has been shown with salmeterol or 122–124 agonists, has been much debated. Caution was formoterol. Where some tolerance to b2- urged over the regular use of all inhaled b2-agonists agonists has been demonstrated in patients with based on the study of regular fenoterol vs. as- asthma who experienced severe attacks,125 this has needed bronchodilator.85 Sears and Taylor113 pro- usually been easy to overcome by increasing the posed the hypothesis that the increased morbidity dose slightly.84 and mortality of asthma over the previous decade Patients taking salmeterol both with ICS92 and was related to increased disease severity, as without ICS126 showed no evidence of reduced evidenced by increased airway responsiveness bronchodilator efficacy over 6 months of study. related to regular inhaled b2-agonist use. The Equally, the FACET study found no evidence of abrupt and striking decrease, not only in asthma deterioration in the control of asthma, and mortality but also in asthma-related hospital although there was an initial decrease in bronch- admissions in New Zealand following the with- odilator efficacy upon addition of formoterol, the drawal of fenoterol in 1990, implied a likely causal improvements in lung function were maintained at relationship between fenoterol and asthma sever- a higher level than with ICS alone for 1 year, ity, rather than cardiac toxicity.2 showing no further evidence of tolerance (Fig. 4).98 A study commissioned by Boehringer Ingleheim, On the other hand, many studies have found the manufacturers of fenoterol, of death and near- evidence for tolerance to the bronchoprotective death events in Saskatchewan, Canada, and the effects of long-acting b2-agonists to allergen or ARTICLE IN PRESS

164 M.R. Sears, J. Lo¨tvall

Figure 4 Increase in FEV1 in patients taking formoterol 9 mg delivered dose twice daily plus budesonide either low dose (100 mg twice daily) or high dose (400 mg twice daily) compared with patients taking the same doses of budesonide alone. Reprinted with permission, copyrightr 1997 Massachusetts Medical Society. All rights reserved.98

non-specific bronchial challenge. However, as Long-term safety of b2-agonists noted by McFadden,119 even where a significant decrease in protective effect was noted, protection There is growing evidence that b2-agonists with still remained greater for the drugs investigated long-acting properties are safe and effective as an than with placebo and never fell below pre- add-on treatment option for patients with asthma treatment baseline values. poorly controlled by low doses of ICS alone. Regular use of long-acting b2-agonists has, Improvements in symptoms do not appear to be however, been linked with tolerance to rapid- made at the expense of a worsening of underlying acting b2-agonists. Several studies have reported control, and systemic adverse effects resulting reduced efficacy of short-acting b2-agonists follow- from prolonged use of high doses of corticosteroids ing treatment with formoterol or salmeterol.127–129 can be reduced.132 The acute administration of a high dose of corticosteroids has, however, been shown to attenuate this effect.49,51,130 van der Woude Future developments in asthma care and colleagues128 indicated that both formoterol and salmeterol reduced the effect of salbutamol b2-receptor gene polymorphisms to a similar extent, whereas van Veen et al.129 It is now known that there are subgroups of asthma showed higher tolerance with salmeterol and patients who experience bronchodilator desensiti- 53 Lee et al. demonstrated higher tolerance with sation related to specific polymorphisms of the b2- formoterol in similar studies comparing the two receptor genes.133 However, while these subgroups 131 long-acting b2-agonists. In contrast, Nelson et al. of patients may experience reduced benefit from and Korosec et al.106 reported no decrease the use of formoterol or salmeterol on a regular in efficacy of salbutamol following treatment basis, there is no evidence that they would not with salmeterol, demonstrating no clinically im- benefit from the rapid onset of formoterol (i.e. if 44 portant tolerance. The interaction between used as needed). Patients with certain b2-recep- long- and short-acting b2-agonists may be asso- tor gene polymorphisms have demonstrated lower ciated with prolonged receptor occupancy by long- airway responsiveness to inhaled salbutamol;40,41 acting b2-agonists, preventing binding by other however, reduced bronchoprotection was not evi- 130 45 b2-agonists. dent in similar patients using formoterol. ARTICLE IN PRESS b2-agonists in asthma management 165

The presence of at least four polymorphisms of b2-agonists used as needed the b2-receptor gene, discussed earlier, each with different properties and resulting in different Although the b2-agonists with long-acting proper- responses to b2-agonist therapy, raises the future ties, formoterol and salmeterol, are playing an possibility of asthma treatments being individually increasing role in combination with ICS in main- tailored to match patient genotypes.32 In this tenance treatment of asthma, a further develop- respect, it is significant that patients have been ment is the use of fast-acting formoterol for use as identified who did not respond to salmeterol but needed for symptom relief. who still responded to formoterol.134–136 Formoterol given by Turbuhaler has as rapid an onset of action as salbutamol administered by pressurised MDI (pMDI).75 Studies have shown that formoterol has a wide safety margin when used as b2-agonists in exercise-induced needed in addition to maintenance dosing. For- bronchoconstriction moterol was well tolerated at daily doses corre- The long duration of action of formoterol and sponding to 90 mg delivered dose in patients with salmeterol should make these drugs more effective stable chronic asthma and without concomitant for protection against exercise-induced broncho- ischaemic heart disease,144 and in patients with constriction (EIB) than the traditional, short-acting acute bronchoconstriction in an emergency room 145 b2-agonists, such as terbutaline and salbutamol. setting. Salmeterol (50 mg single dose) has been shown to A randomised, double-blind, parallel-group, 3- protect against EIB for more than 12 h;137,138 month study compared formoterol 6 mg with terbu- although the protective effect of salmeterol does taline 0.5 mg (both delivered by Turbuhaler) taken decrease when the drug is taken regularly.139 as needed.124 ln this study, patients had moderate- Similarly, single doses of formoterol delivered by to-severe asthma requiring as-needed medication Turbuhaler (6 and 12 mg) gave significantly ðPo0:05Þ despite taking an ICS. Patients given formoterol as better and longer protection against EIB in adults140 reliever medication experienced a significantly and children141 compared with terbutaline 0.5 mg. ðP ¼ 0:013Þ longer time to first severe exacerbation Formoterol had about three-times longer duration (Fig. 5), had greater improvement in lung function of effect than the short-acting bronchodilators and took fewer inhalations of this as-needed normally used to protect against EIB.141 medication, compared with patients given terbuta- Regular use of inhaled b2-agonists can result in a line. Both treatments were well tolerated, with no reduction in the protective effect that they offer statistically significant differences between the against bronchoconstrictor stimuli. In one clinical two treatment groups in electrocardiographic find- trial, for example, patients with EIB received either ings, serum potassium concentration or adverse formoterol or placebo twice daily for 4 weeks and events. performed two cycle ergometer tests, 30 min apart, on days 1, 14 and 28; a dose of formoterol was taken 30 min before the second test. Signifi- cant tolerance to the protective effect of formo- terol was evident in the formoterol patients, but not in the placebo patients, at days 14 and 28 (P ¼ 0:012 for both occasions).142 This is echoed in a meta analysis of corticosteroid-treated patients with asthma.50 In patients with the Arg16 poly- morphism, 1–2 weeks of treatment with formoterol was less effective than placebo. A study of patients with EIB compared the effects of salmeterol with the leukotriene receptor agonist montelukast.143 This study demonstrated tolerance to the protec- tive effect of salmeterol but not to montelukast over an 8-week period. Tolerance, however, is a class effect that is shared by all b2-agonists and, Figure 5 Kaplan–Meier plot showing estimated probabil- although the bronchoprotective effect is slightly ity of remaining without severe exacerbation in patients reduced with regular dosing, a clinically significant taking formoterol 4:5 mg inhaled dose or inhaled terbuta- level of bronchoprotection remains in the majority line 0.5 mg as needed. Reprinted with permission from of patients. Elsevier.123 ARTICLE IN PRESS

166 M.R. Sears, J. Lo¨tvall

Earlier short studies that compared formoterol as of choice, the b2-agonists have shown a continuous needed with salbutamol all demonstrated greater evolution, with compounds offering progressively improvement in asthma control with formoter- increasing selectivity, combined with faster onset ol.146–148 A recently published, 6-month, real-life and longer duration of action. This is reflected in study comparing formoterol and salbutamol as the most recent update of the GINA guidelines, reliever medication provided further evidence of which has reclassified the traditional short-and the efficacy of formoterol as needed, with a long-acting b2-agonists into rapid-and/or long-act- 64 significant ðPo0:001Þ reduction in the risk of ing b2-agonists. asthma exacerbations compared with salbuta- Although salbutamol is widely used as reliever mol.149 This study was powered primarily for safety medication for acute bronchoconstriction, its short outcomes ðn ¼ 18; 132Þ and confirmed that formo- duration of action makes it less appropriate for terol used as needed had a safety profile similar to regular use and unsuitable for relieving night-time that of salbutamol. symptoms. Drugs with a longer duration of action, There is thus strong evidence that formoterol’s such as salmeterol and formoterol, are more unique combination of long duration and fast onset appropriate in these circumstances. The combina- makes it suitable not only for regular maintenance tion of the rapid onset and long duration of treatment in asthma (in combination with ICS) but formoterol provides prompt and long-lasting symp- also for use as needed. Formoterol has recently tom relief for patients, combined with fewer gained FDA approval for use as a rescue medica- exacerbations. Further research is needed to assess tion. This is reflected in the current Global the benefits that this agent may have in terms of Initiative for Asthma (GINA) guidelines, which has patient quality of life and the economic burden of revised its classification of b2-agonists to rapid- the disease. acting and/or long-acting.64 ln the clinical setting, the rapid onset of action of formoterol enabling as- needed use may become equally as important as its property of a long duration of action. References

Can b2-agonists be used as monotherapy? Neither short-acting nor long-acting b -agonists are 1. Barnes PJ. Pathophysiology of asthma. Br J Clin Pharmacol 2 1996;42:3–10. currently recommended as monotherapy in pa- 2. Sears MR. Epidemiological trends in asthma. Can Respir tients with persistent asthma because of a per- J 1996;3:261–8. ceived lack of anti-inflammatory activity.4,5,64,83 3. MMWR: Morbidity and Mortality Weekly Rep 1998;47:SS-1. Most studies have found no convincing evidence of 4. Boulet L-P, Bai TR, Becker A, et al. What is new since the reduction in inflammatory cell infiltrates in airway last (1999) Canadian Asthma Consensus Guidelines? Can Respir J 2001;8(Suppl. A):5A–27A. walls or in secretions following use of these agents. 5. Boulet LP, Becker A, Berube D, Beveridge R, Ernst P. Some studies have suggested that treatment with Canadian Asthma Consensus Report, 1999. Canadian Asth- 150 151 formoterol and with salmeterol can reduce ma Consensus Group. CMAJ 1999;161(11 Suppl.):S1–61. some markers of airway inflammation in patients 6. Haahtela T. Advances in Pharmacotherapy of asthma. Curr with asthma and have suggested the intriguing Probl Dermatol 1999;28:135–52. possibility that these drugs may, in fact, be capable 7. Sakula A. A history of asthma. J R Coll Phys (London) 1988;22:36–44. of independent anti-inflammatory action. Likewise, 8. Chen KK, Schmidt CF. Ephedrine and related substances. recent research has suggested that there may be Medicine (Baltimore) 1930;9:1–117. interactions between long-acting b2-agonists and 9. Solis-Cohen S. The use of adrenal substances in the corticosteroids at the cellular levels.152 More treatment of asthma. J Am Med Assoc 1900;34:1164–6. research is needed to determine whether this is 10. Goldie RG, Lulich KM, Paterson JW. Bronchodilators: beta- agonists. Med J Aust 1995;162:100–2. relevant to the clinical use of these b2-agonists. 11. Benson RL, Perlman F. Clinical effects of epinephrine by inhalation. J Allergy 1948;19:129–40. 12. Gay LN, Long JW. Clinical evaluation of isopropylepinephr- ine in management of bronchial asthma. J Am Med Assoc Conclusions 1949;139:452–7. 13. Paterson JW, Woolcock AJ, Shenfield GM. Bronchodilator Whether used prophylactically, as needed, or drugs. Am Rev Respir Dis 1979;120:1149–88. regularly in combination with ICS, b -agonists have 14. Ahlquist RP. A study of the adrenotropic receptors. Am 2 J Physiol 1948;153:586–600. played a significant role in the treatment of asthma 15. Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown Jr TG. since they were first introduced nearly half a Differentiation of receptor systems activated by sympatho- century ago. Although each era has had its drug mimetic amines. Nature 1967;214:597–8. ARTICLE IN PRESS b2-agonists in asthma management 167

16. Emilien G, Maloteaux JM. Current therapeutic uses and 39. Ramsay CE, Hayden CM, Tiller KJ, Burton PR, Goldblatt J,

potential of beta-adrenoceptor agonists and antagonists. Lesouef PN. Polymorphisms in the b2-adrenoreceptor gene Eur J Clin Pharmacol 1998;53:389–404. are associated with decreased airway responsiveness. Clin 17. Newhouse MT, Dolovich MB. Control of asthma by aerosols. Exp Allergy 1999;29:1195–203.

N Engl J Med 1986;315:870–4. 40. Kotani Y, Nishimura Y, Maeda H, Yokoyama M. Beta2- 18. Frielle T, Daniel KW, Caron MG, Lefkowitz RJ. Structural adrenergic receptor polymorphisms affect airway respon- basis of b-adrenergic receptor subtype specificity studies siveness to salbutamol in asthmatics. J Asthma 1999;36: with chimeric b1=b2-adrenergic receptors. Proc Natl Acad 583–90. Sci USA 1988;85:9494–8. 41. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self TH, 19. Kobilka BK, Dixon RAF, Frielle T, et al. cDNA for the human Johnson JA. Impact of genetic polymorphisms of the b2- b2-adrenergic receptor: a protein with multiple mem- adrenergic receptor on albuterol bronchodilator pharma- brane-spanning domains and encoded by a gene whose codynamics. Clin Pharmacol Ther 1999;65:519–25. chromosomal location is shared with that of the receptor 42. Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic for platelet-derived growth factor. Proc Natl Acad Sci USA polymorphisms of the b2-adrenergic receptor in nocturnal 1987;84:46–50. and nonnocturnal asthma: evidence that Gly16 correlates 20. Anderson GP, Linde´n A, Rabe KF. Why are long-acting beta- with the nocturnal phenotype. J Clin Invest 1995;95: adrenoceptor agonists long-acting? Eur Respir J 1994;7: 1635–41. 569–78. 43. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the b2- 21. Spina D, Rigby PJ, Paterson JW, Goldie RG. Autoradio- adrenoceptor and the response to long-term b2-agonist graphic localization of beta adrenoceptors in asthmatic therapy in asthma. Eur Respir J 1998;11:589–93. human lung. Am Rev Respir Dis 1989;140:1410–5. 44. Lipworth BJ, Hall IP, Aziz I, Tan S, Wheatley A. b2- 22. Barnes PJ. Beta adrenergic receptors and their regulation. adrenoceptor polymorphism and bronchoprotective sensi- Am J Respir Crit Care Med 1995;152:838–60. tivity with regular short-and long-acting b2-agonist ther- 23. Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic apy. Clin Sci (London) 1999;96:253–9. visualization of beta-adrenoceptor subtypes in human lung. 45. Lipworth BJ, Hall IP, Tan S, Aziz I, Coutie W. Effects of Am Rev Respir Dis 1985;132:541 7. – genetic polymorphism on ex vivo and in vivo function of b - 24. Johnson M. The beta-adrenoceptor. Am J Respir Crit Care 2 adrenoceptors in asthmatic patients. Chest 1999;115: Med 1998;158:S146–53. 324–8. 25. Qing F, Rahman SU, Rhodes CG, et al. Pulmonary and 46. Lipworth BJ, Dempsey OJ, Aziz I. Functional antagonism cardiac b-adrenoceptor density in vivo in asthmatic with formoterol and salmeterol in asthmatic patients subjects. Am J Respir Crit Care Med 1997;55:1130–4. expressing the homozygous glycine-16 beta(2)-adrenocep- 26. Lipworth BJ, McDevitt DG. Inhaled b -adrenoceptor ago- 2 tor polymorphism. Chest 2000;118:321–8. nists in asthma: help or hindrance? Br J Clin Pharmacol 47. Taylor DR, Drazen JM, Herbison GP,Yandava CN, Hancox RJ, 1992;33:129–38. Town GI. Asthma exacerbations during long term b-agonist 27. Robinson GA, Butcher RW, Sutherland EW. Adenyl cyclase as use: influence of b adrenoceptor polymorphism. Thorax an adrenergic receptor. Ann N Y Acad Sci 1967;319:703–23. 2 2000;55:762–7. 28. Lefkowitz RJ. G protein-coupled receptors. III. New roles 48. Israel E, Drazen JM, Liggett SB, et al. Effect of polymorph- for receptor kinases and beta-arrestins in receptor signal- ism of the b -adrenergic receptor on response to regular ing and desensitization. J Biol Chem 1998;273:18677–80. 2 use of albuterol in asthma. Int Arch Allergy Immunol 29. Scola AM, Chong LK, Suvarna SK, Chess-Williams R, Peachell PT. Desensitisation of mast cell beta2-adrenoceptor- 2001;124:183–6. mediated responses by salmeterol and formoterol. Br 49. Tan KS, Grove A, McLean A, Gnosspelius Y, Hall IP, Lipworth J Pharmacol 2004;141:163–71. BJ. Systemic corticosteroid rapidly reverses bronchodilator 30. Jones SL, Cowan JO, Flannery EM, Hancox RJ, Herbison GP, subsensitivity induced by formoterol in asthmatic patients. Taylor DR. Reversing acute bronchoconstriction in asthma: Am J Respir Crit Care Med 1997;156:28–35. the effect of bronchodilator tolerance after treatment 50. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ. The with formoterol. Eur Respir J 2001;17:368–73. arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated 31. Liggett SB. Polymorphisms of the b2-adrenergic receptor and asthma. Am J Respir Crit Care Med 1997;156:S156–62. with formoterol and salmeterol. Br J Clin Pharmacol 2004;57:68–75. 32. Liggett SB. b2-adrenergic receptor pharmacogenetics. Am J Respir Crit Care Med 2000;161:S197–201. 51. Jackson CM, Lipworth B. Benefit-risk assessment of long- 33. Walters EH, Walters JA. A genetic twist to the b-agonist acting beta2-agonists in asthma. Drug Saf 2004;27:243–70. ‘debate’. Clin Sci (London) 1999;96:219–20. 52. Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region beta 2-adrenergic receptor 34. Liggett SB. Genetics of b2-adrenergic receptor variants in asthma. Clin Exp Allergy 1995;25(Suppl. 2):89–94. haplotypes alter receptor expression and predict in vivo 35. Liggett SB. The pharmacogenetics of beta2-adrenergic responsiveness. Proc Natl Acad Sci USA 2000;97:10483–8. receptors: relevance to asthma. J Allergy Clin Immunol 53. Lipworth B, Koppelman GH, Wheatley AP, et al. Beta2 2000;105:S487–92. adrenoceptor promoter polymorphisms: extended haplo-

36. Weir TD, Mallek N, Sandford AJ, et al. b2-adrenergic types and functional effects in peripheral blood mono- receptor haplotypes in mild, moderate and fatal/near fatal nuclear cells. Thorax 2002;57:61–6. asthma. Am J Respir Crit Care Med 1998;158:787–91. 54. Heel RC, Brogden RN, Speight TM, Avery GS. Fenoterol: a

37. Hall IP. b2-adrenoceptor polymorphisms and asthma. Clin review of its pharmacological properties and therapeutic Exp Allergy 1999;29:1151–4. efficacy in asthma. Drugs 1978;15:3–32. 38. Hall IP,Wheatley A, Wilding P,Liggett SB. Association of Glu 55. Zidek R. Comparative investigations of Berotec, Alupent

27 b2-adrenoceptor polymorphism with lower airway and Aludrin in asthmatic dyspnea. Int J Clin Pharmacol reactivity in asthmatic subjects. Lancet 1995;345:1213–4. 1971;4(Suppl.):145. ARTICLE IN PRESS

168 M.R. Sears, J. Lo¨tvall

56. Nelson HS. Beta adrenergic bronchodilators. N Engl J Med 77. Rhodes DG, Newton R, Butler R, Herbette L. Equilibrium 1995;333:499–506. and kinetic studies of the interactions of salmeterol with 57. Price AH, Clissold SP.Salbutamol in the 1980s: a reappraisal membrane bi-layers. Mol Pharmacol 1992;42:596–602. of its clinical efficacy. Drugs 1989;38:77–122. 78. Johnson M, Butchers PR, Coleman RA, et al. The pharma- 58. Johnson M. Salmeterol. Med Res Rev 1995;15:225–57. cology of salmeterol. Life Sci 1993;52:2131–43. 59. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison 79. Green SA, Spasoff AP, Coleman RA, Johnson M, Liggett SB. of racemic albuterol and levalbuterol for treatment of Sustained activation of a G protein-coupled receptor via acute asthma. J Pediatr 2003;143:731–6. ‘‘anchored’’ agonist binding. Molecular localization of the 60. Scott VL, Frazee LA. Retrospective comparison of nebulized salmeterol exosite within the 2-adrenergic receptor. J Biol levalbuterol and albuterol for adverse events in patients Chem 1996;271:24029–35. with acute airflow obstruction. Am J Ther 2003;10:341–7. 80. Bergendal A, Linden A, Skoogh BE, Gerspacher M, Anderson 61. Berger WE. Levalbuterol: pharmacologic properties and use GP, Lo¨fdahlCG. Extent of salmeterol-mediated reassertion in the treatment of pediatric and adult asthma. Ann Allergy of relaxation in guinea-pig trachea pretreated with Asthma Immunol 2003;90:583–91. aliphatic side chain structural analogues. Br J Pharmacol 62. Ahrens R, Weinberger M. Levalbuterol and racemic albu- 1996;117:1009–15. terol: are there therapeutic differences? J Allergy Clin 81. Linden A, Bergendal A, Ullman A, Skoogh BE, Lo¨fdahlCG. Immunol 2001;108:681–4. Salmeterol, formoterol, and salbutamol in the isolated 63. Lo¨tvallJ, Palmqvist M, Arvidsson P, Maloney A, Ventresca guinea pig trachea: differences in maximum relaxant GP, Ward J. The therapeutic ratio of R-albuterol is effect and potency but not in functional antagonism. comparable with that of RS-albuterol in asthmatic pa- Thorax 1993;48:547–53. tients. J Allergy Clin Immunol 2001;108:726–31. 82. Rabe KF, Giembycz MA, Dent G, Perkins RS, Evans P, Barnes 64. Global Initiative for Asthma (GINA). Global Strategy for PJ. Salmeterol is a competitive antagonist at beta- Asthma Management and Prevention: WHO/NHLBI Work- adrenoceptors mediating inhibition of respiratory burst in shop report. National Institutes of Health, National Heart, guinea-pig eosinophils. Eur J Pharmacol 1993;231:305–8. Lung and Blood Institute (NHLBI). Publication Number 83. British Thoracic Society; Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. 02-3659 2002 (Updated 2003). Thorax 2003; 58 (Suppl.1 ):i1–i94. 65. Hardman JG, Limbird LE, editors. Gondman & Gilman’s the 84. Svedmyr N, Lo¨fdahlCG. The use of beta2-adrenoceptor pharmacological basis of therapeutics, International ed. agonists in the treatment of bronchial asthma. Pharmacol New York: McGraw Hill; 1996. p. 214. Toxicol 1996;78:3–11. 66. Persson H. The research behind terbutaline. Pharmacol 85. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta- Toxicol 1995;77(Suppl. 3):16–20. agonist treatment in bronchial asthma. Lancet 1990;336: 67. Crompton GK, Ayres JG, Basran G, et al. Comparison of oral 1391–6. bambuterol and inhaled salmeterol in patients with 86. Taylor TD, Sears MR, Herbison GP, et al. Regular inhaled b symptomatic asthma and using inhaled corticosteroids. agonist in asthma: effects on exacerbations and lung Am J Respir Crit Care Med 1999;159:824–8. function. Thorax 1993;48:134–8. 68. Moore RH, Khan A, Dickey BF. Long-acting inhaled 87. Ellman MS, Viscoli CM, Sears MR, Taylor DR, Beckett WS, b -agonists in asthma therapy. Chest 1998;113:1095–108. 2 Horwitz RI. A new index of prognostic severity for chronic 69. Lo¨fdahlC-G, Svedmyr N. Formoterol fumarate, a new beta 2 asthma. Chest 1997;112:582–90. adrenoreceptor agonist: acute studies of selectivity and 88. Shepherd GL, Hetzel MR, Clark TJ. Regular versus sympto- duration of effect after inhaled and oral administration. matic aerosol bronchodilator treatment of asthma. Br J Dis Allergy 1989;44:264 71. – Chest 1981;75:215–7. 70. Anderson GP. Long-acting inhaled beta adrenoreceptor 89. Drazen JM, Israel E, Boushey HA, et al. Comparison of agonists: the comparative pharmacology of formoterol regularly scheduled with as-needed use of albuterol in mild and salmeterol. Agents Actions Suppl 1993;43:253–69. asthma. N Engl J Med 1996;335:841–7. 71. Anderson GP.Formoterol: pharmacology, molecular basis of 90. Jenkins CR. Long-acting beta2-agonists: the new symptom agonism, and mechanism of long duration of a highly potent controllers for asthma. Med J Aust 1999;171:255–8. and selective b2-adrenoceptor agonist bronchodilator. Life 91. Lemanske Jr RF, Sorkness CA, Mauger EA, et al. Asthma Sci 1993;52:2145–60. Clinical Research Network for the National Heart Lung, and 72. Tattersfield AE. Clinical pharmacology of long-acting Blood Institute. Inhaled corticosteroid reduction and b-receptor agonists. Life Sci 1993;52:2161–9. elimination in patients with persistent asthma receiving 73. Palmqvist M, Persson G, Lazer L, Rosenborg J, Larsson P, salmeterol: a randomized controlled trial. J Am Med Assoc Lo¨tvallJ. Inhaled dry powder formoterol and salmeterol in 2001;285:2594–603. asthmatic patients: onset of action, duration of effect and 92. Greening AP, Ind PW, Northfield M, Shaw G. Added potency. Eur Respir J 1997;10:2484–9. salmeterol versus higher-dose corticosteroid in asthma 74. van Noord JA, Smeets JJ, Raaijmakers JA, Bommer AM, patients with symptoms on existing inhaled corticosteroid. Maesen FP. Salmeterol versus formoterol in patients with Lancet 1994;344:219–24. moderately severe asthma: onset and duration of action. 93. Woolcock A, Lundback B, Ringdal N, Jacques LA. Compar- Eur Respir J 1996;9:1684–8. ison of addition of salmeterol to inhaled steroids with 75. Seberova´ E, Andersson A. Oxis (formoterol given by doubling of the dose of inhaled steroids. Am J Respir Crit Turbuhaler) showed as rapid an onset of action as Care Med 1996;153:1481–8. salbutamol given by a pMDI. Respir Med 2000;94:607–11. 94. Pearlman DS, Strieker W, Weinstein S, et al. Inhaled 76. Naline E, Zhang Y, Qian Y, et al. Relaxant effects and salmeterol and fluticasone: a study comparing monother- durations of action of formoterol and salmeterol on the apy and combination therapy in asthma. Ann Allergy isolated human bronchus. Eur Respir J 1994;7:914–20. Asthma Immunol 1999;82:257–65. ARTICLE IN PRESS b2-agonists in asthma management 169

95. Condemi JJ, Goldstein S, Kalberg C, Yancey S, Emmett A, 115. Pearce N, Beasley R, Crane J, Burgess C, Jackson R. End of Rickard K. The addition of salmeterol to fluticasone the New Zealand asthma mortality epidemic. Lancet propionate versus increasing the dose of fluticasone 1995;345:41–4. propionate in patients with persistent asthma. Ann Allergy 116. Wooltorton E. Salmeterol (Serevent) asthma trial halted Asthma Immunol 1999;82:383–9. early. CMAJ 2003;168:738. 96. D’Urzo AD, Chapman KR, Cartier A, Hargreave FE, 117. Spitzer WO, Suissa S, Ernst P, et al. The use of b-agonists Fitzgerald M, Tesarowski D. Effectiveness and safety of and the risk of death and near death from asthma. N Engl J salmeterol in nonspecialist practice settings. Chest Med 1992;326:501–6. 2001;119:714–9. 118. Suissa S, Ernst P, Boivin J-F, et al. A cohort analysis 97. Masoli M, Weatherall M, Holt S, Beasley R. Clinical of excess mortality in asthma and the use of inhaled dose–response relationship of fluticasone propionate in b-agonists. Am J Respir Crit Care Med 1994;149:604–10.

adults with asthma. Thorax 2004;59:16–20. 119. McFadden Jr ER. The b2-agonist controversy revisited. Ann 98. Pauwels RA, Lo¨fdahl C-G, Postma DS, et al. Effect of Allergy Asthma Immunol 1995;75:173–6. inhaled formoterol and budesonide on exacerbations of 120. Pearlman DS, Chervinsky P, La Force C, et al. A comparison asthma. N Engl J Med 1997;337:1405–11. of salmeterol with albuterol in the treatment of mild-to- 99. Bouros D, Bachlitzanakis N, Kottakis J, et al. Formoterol moderate asthma. N Engl J Med 1992;327:1420–5. and beclomethasone versus higher dose beclomethasone as 121. D’Alonzo GB, Nathan RA, Henochowicz S, et al. Salmeterol maintenance therapy in adult asthma. Eur Resp xinafoate as maintenance therapy compared with albuterol J 1999;14:627–32. in patients with asthma. J Am Med Assoc 1994;271:1412–6. 100. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose 122. Ekstro¨mT, Ringdal N, Sobradillo V, Runnerstro¨mE, Soliman inhaled budesonide and formoterol in mild persistent S. Low-dose formoterol Turbuhaler (Oxis) bid, a 3-month asthma: the OPTIMA randomized trial. Am J Respir Crit placebo-controlled comparison with terbutaline (qid). Care Med 2001;164:1392–7. Respir Med 1998;92:1040–5. 101. Lipworth BJ, Clark DJ. Effects of airway calibre on lung 123. Ekstro¨mT, Ringdal N, Tukiainen P, Runnerstrom E, Soliman delivery of nebulised salbutamol. Thorax 1997;52:1036–9. S. A 3-month comparison of formoterol with terbutaline via 102. Larj MJ, Bleecker ER. Effects of beta2-agonists on airway Turbuhaler. A placebo-controlled study. Ann Allergy Asthma tone and bronchial responsiveness. J Allergy Clin Immunol Immunol 1998;81:225–30. 2002;110:S304–12. 124. Tattersfield AE, Lo¨fdahlC-G, Postma DS, et al. Comparison 103. Abramson MJ, Walters J, Walters EH. Adverse effects of of formoterol and terbutaline for as-needed treatment of beta-agonists: are they clinically relevant. Am J Respir Med asthma: a randomised trial. Lancet 2001;357:257–61. 2003;2:287–97. 125. Pansegrouw DF, Weich DJ, le Roux FPJ. Beta-adrenergic 104. Tan KS, McFarlane LC, Lipworth BJ. Concomitant adminis- receptor tachyphylaxis in acute severe asthma. S Afr Med tration of low-dose prednisolone protects against in vivo J 1991;80:229–30. beta2-adrenoceptor subsensitivity induced by regular for- 126. Rosenthal RR, Busse WW, Kemp JP, et al. Effect of long- moterol. Chest 1998;113:34–41. term salmeterol therapy compared with as-needed albu- 105. Lipworth BJ, Aziz I. Bronchodilator response to albuterol terol use on airway hyperresponsiveness. Chest 1999;116: after regular formoterol and effects of acute corticosteroid 595–602. administration. Chest 2000;117:156–62. 127. Lipworth BJ, Aziz I. A high dose of albuterol does not 106. Korosec M, Novak RD, Myers E, Skowronski M, McFadden Jr overcome bronchoprotective subsensitivity in asthmatic ER. Salmeterol does not compromise the bronchodilator subjects receiving regular salmeterol or formoterol. response to albuterol during acute episodes of asthma. Am J Allergy Clin Immunol 1999;103:88–92. J Med 1999;107:209–13. 128. van der Woude HJ, Winter TH, Aalbers R. Decreased 107. Stolley PD, Schinnar R. Association between asthma bronchodilating effect of salbutamol in relieving metha- mortality and isoproterenol aerosols: a review. Prev Med choline induced moderate to severe bronchoconstriction 1978;7:519–38. during high dose treatment with long acting beta2 agonists. 108. Crane J, Flatt A, Jackson R, et al. Prescribed fenoterol and Thorax 2001;56:529–35. death from asthma in New Zealand, 1981–1983: case- 129. van Veen A, Weller FR, Wierenga EA, Jansen HM, Jonkers control study. Lancet 1989;1:917–22. RE. A comparison of salmeterol and formoterol in attenu- 109. Grant IW. Fenoterol and asthma deaths in New Zealand. NZ ating airway responses to short-acting beta2-agonists. Med J 1990;103:160–1. Pulm Pharmacol Ther 2003;16:153–61. 110. Wilson JD. Selective prescribing of fenoterol and saibuta- 130. Aziz I, Lipworth BJ. In vivo effect of albuterol on mol in New Zealand in general practice. Postmarketing methacholine-contracted bronchi in conjunction with Surveillance 1991;5:105–18. salmeterol and formoterol. J Allergy Clin Immunol 111. Pearce N, Grainger J, Atkinson M, et al. Case-control study 1999;103:816–22. of prescribed fenoterol and death from asthma in New 131. Nelson HS, Berkowitz RB, Tinkelman DA, Emmett AH, Zealand, 1977–1981. Thorax 1990;45:170–5. Rickard KA, Yancey SW. Lack of subsensitivity to albuterol 112. Grainger J, Woodman K, Pearce N, et al. Prescribed after treatment with salmeterol in patients with asthma. fenoterol and death from asthma in New Zealand, Am J Respir Crit Care Med 1999;159:1556–61. 1981–7: a further case-control study. Thorax 1991;46: 132. Redington AE, Rees PJ. Long-acting inhaled beta2-agonists 105–11. in the management of asthma: recent advances and

113. Sears MR, Taylor DR. The b2-agonist controversy. Observa- current recommendations. Int J Clin Pract 1998;52:482–6. tions, explanations and relationship to asthma epidemiol- 133. Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association

ogy. Drug Saf 1994;11:259–83. between b2-adrenoceptor polymorphism and susceptibility 114. Sears MR. Short-acting beta-agonist research: a perspec- to bronchodilator desensitisation in moderately severe tive. 1997. Can Respir J 2001;8:349–55. stable asthmatics. Lancet 1997;350:995–9. ARTICLE IN PRESS

170 M.R. Sears, J. Lo¨tvall

134. Ulrik CS, Kok-Jensen A. Different bronchodilating effect of exercise-induced bronchoconstriction. A randomized, dou- salmeterol and formoterol in an adult asthmatic. Eur Respir ble-blind trial. Exercise Study Group. Ann Intern Med J 1994;7:1003–5. 2000;132:97–104. 135. Bartuschka B, Querfurt H, Ortland C, Petermann W. 144. To¨ttermanKJ, Huhti L, Sutinen E, et al. Tolerability to high Formoterol Turbuhaler shows bronchodilating efficacy in doses of formoterol and terbutaline via Turbuhaler for 3 patients not responding to salmeterol Diskus. Am J Respir days in stable asthmatic patients. Eur Respir J Crit Care Med 2000;161(No. 3, Pt 2):A190. 1998;12:573–9. 136. Bousquet J, Meziane H, Le Gros V, Bourdeix I. Efficacy of 145. Malolepszy J, Bo¨szo¨rme´ny Nagy G, Selroos O, Larsson P, formoterol in asthmatic patients sub-optimally controlled Brander R. Safety of formoterol Turbuhaler at cumulative with salmeterol. Am J Respir Crit Care Med dose of 90 mg in patients with acute bronchoconstriction. 2001;163(Suppl. 5):A589. Eur Respir J 2001;18:928–34. 137. Bronsky EA, Pearlman DS, Pobiner BF, Scott C, Wang Y, Sta˚hl 146. Wallin A, Melander B, Rosenhall L, Sandstrom T, Wa˚hlander E. Prevention of exercise-induced bronchospasm in pedia- L. Formoterol, a new long-acting beta2 agonist for tric asthma patients: a comparison of two salmeterol inhalation twice daily, compared with salbutamol in the powder delivery devices. Pediatrics 1999;104:501 6. – treatment of asthma. Thorax 1990;45:259–61. 138. Blake K, Pearlman DS, Scott C, Wang Y, Sta˚hlE, Arledge T. 147. Arvidsson P, Larsson S, Lo¨fdahlC-G, Melander B, Svedmyr Prevention of exercise-induced bronchospasm in pediatric N, Wa˚hlanderL. Inhaled formoterol during one year in asthma patients: a comparison of salmeterol powder with asthma: a comparison with salbutamol. Eur Respir J albuterol. Ann Allergy Asthma Immunol 1999;82:205–11. 1991;4:1168–73. 139. Simons FE, Gerstner TV, Cheang MS. Tolerance to the 148. Midgren B, Melander B, Persson G. Formoterol, a new long- bronchoprotective effect of salmeterol in adolescents with acting beta-2 agonist, inhaled twice daily, in stable exercise-induced asthma using concurrent inhaled gluco- asthmatic subjects. Chest 1992;101:1019–22. corticoid treatment. Pediatrics 1997;99:655–9. 140. Vilsvik J, Ankerst J, Palmqvist M, et al. Protection against 149. Pauwels RA, Sears MR, Campbell M, et al. Formoterol as cold air and exercise-induced bronchoconstriction while on relief medication in asthma: a worldwide safety and regular treatment with Oxis. Respir Med 2001;95:484–90. effectiveness trial. Eur Respir J 2003;22:787–94. 141. Grønnerød TA, von Berg A, Schwabe G, Soliman S. 150. Wallin A, Sandstrom T, Soderberg M, et al. The effects of Formoterol via Turbuhalers gave better protection than regular inhaled formoterol, budesonide and placebo on terbutaline against repeated exercise challenge for up to mucosal inflammation and clinical indices of mild asthma. 12 hours in children and adolescents. Respir Med Am J Respir Crit Care Med 1998;159:79–86. 2000;94:661–7. 151. Dente FL, Bancalari L, Bacci E, et al. Effect of a single dose 142. Garcia R, Guerra P, Feo F, et al. Tachyphylaxis following of salmeterol on the increase in airway eosinophils induced regular use of formoterol in exercise-induced bronchos- by allergen challenge in asthmatic subjects. Thorax pasm. J Investig Allergol Clin Immunol 2001;11:176–82. 1999;54:622–4. 143. Edelman JM, Turpin JA, Bronsky EA, Grossman J, Kemp JP, 152. Barnes PJ. Scientific rationale for inhaled combination Ghannam AF, DeLucca PT, Gormley GJ, Pearlman DS. Oral therapy with long-acting b2-agonists and corticosteroids. montelukast compared with inhaled salmeterol to prevent Eur Respir J 2002;19:182–91.